Low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug. Increasing the bioavailability of low-solubility drugs has been the subject of much research. Increasing bioavailability depends on improving the concentration of dissolved drug in solution to improve absorption.
It is well known that the amorphous form of a low-solubility drug that is capable of existing in either the crystalline or amorphous form may temporarily provide a greater aqueous concentration of drug relative to the equilibrium concentration obtained by dissolution of the drug in a use environment. Such amorphous forms may consist of the amorphous drug alone, a dispersion of the drug in a matrix material, or the drug adsorbed onto a substrate. It is believed that such amorphous forms of the drug may dissolve more rapidly than the crystalline form, often dissolving faster than the drug can precipitate from solution. As a result, the amorphous form may temporarily provide a greater-than-equilibrium concentration of drug.
While such amorphous forms may show initially enhanced concentration of the drug in a use environment, nevertheless the improved concentration is often short-lived. Typically, the initially enhanced drug concentration is only temporary and quickly returns to the lower equilibrium concentration.
One approach to increase the bioavailability of low-solubility drugs has involved forming amorphous dispersions of drugs with polymers. Examples of attempts to increase drug concentration by forming a dispersion of the drug with a polymer include Nakamichi et al. U.S. Pat. No. 5,456,923 and Curatolo et al. EP 0901786A2.
When formulating such solid amorphous dispersions into immediate release solid dosage forms for oral administration to a use environment such as the GI tract of an animal such as a human, it is often desirable to maximize the amount of dispersion present in the dosage form. This minimizes the size of the solid dosage form required to achieve the desired dose. Depending on the drug dose, it is often desired that the solid amorphous dispersion comprise at least 30 wt %, preferably at least 40 wt %, and more preferably at least 50 wt % or more of the solid dosage form. Such high drug loadings of dispersion in a solid dosage form minimize the dosage form's size, making it easier for the patient to swallow it and tending to improve patient compliance.
For the ideal immediate release dosage form, the dosage form should have high strength and durability in the solid state, but when ingested, the tablet should rapidly disintegrate and disperse the drug. It is well known how to achieve durability and rapid disintegration for conventional crystalline bulk drug. However, the physical properties of solid amorphous dispersions are very different than conventional crystalline bulk drug, leading to difficulties in imparting such characteristics to dosage forms containing dispersions.
Specifically, in the solid state, solid amorphous dispersions undergo plastic deformation rather than fracture when compressed into a tablet. This can lead to unacceptably low tablet porosity. In addition, when compressed, solid amorphous dispersions adhere better than conventional crystalline bulk drug, due to their plastic flowability and strong surface interactions. The low porosity obtained when solid amorphous dispersions are compressed into a tablet made using conventional tableting formulations leads to slow wicking of water into the tablet, also slowing tablet disintegration. Additionally, when administered to an aqueous environment of use, solid amorphous dispersions can form strong hydrogels, thereby inhibiting rapid tablet disintegration.
The inventors have found that conventional methods of formulating immediate release dosage forms are inappropriate for formulating immediate release dosage forms of solid amorphous dispersions. Specifically, when immediate release tablets comprising a solid amorphous dispersion of a low-solubility drug and a concentration-enhancing polymer are formulated using conventional amounts of tableting excipients used to form conventional immediate release dosage forms, the dosage forms disintegrate too slowly and/or reach maximum concentration in solution too slowly. This problem increases with increasing amount of solid amorphous dispersion in the tablet, particularly when the solid amorphous dispersion content in the tablet reaches approximately 30 to 50% of the total tablet mass. As a result, conventional tablet formulations cannot be used to obtain immediate release dosage forms containing high loadings of such solid amorphous dispersions.
Dosage forms containing solid amorphous dispersions of a specific low solubility drug and concentration-enhancing polymers are disclosed in commonly assigned copending U.S. patent application Ser. No. 09/808,559 filed Mar. 14, 2001. However, no guidelines for selecting excipients for use in forming immediate release dosage forms are provided.
Butler U.S. Pat. No. 5,985,326 discloses the formation of dosage forms containing solid dispersions of two specific poorly soluble drugs in a polymer, the dispersion being formed by coprecipitation of the drug and polymer. Tablets comprising up to 40 wt % of the dispersion were prepared using conventional amounts of conventional tableting excipients. Butler is silent on the disintegration rate or dissolution rate of drug from these dosage forms.
Thus, there is a need in the art for immediate release dosage forms containing large amounts of solid amorphous dispersions that are non-friable, while at the same time exhibiting rapid disintegration and dissolution of the drug.